The vinca alkaloids are, in general, dimeric indole-dihydroindole compounds. Two of the alkaloids obtained from the leaves of the plant Vinca rosea, vincristine (VCR) and vinblastine (VLB), are marketed for the treatment of leukemias and related neoplasms in humans. A third compound, an amide derivative of vinblastine called vindesine (VDS), is marketed for the treatment of neoplastic diseases in humans in several European countries and is on clinical trial in the United States. These three drugs are described in U.S. Pat. Nos. 3,205,220 (vincristine), 3,097,137 (vinblastine), and 4,203,898 (vindesine). The drugs are administered by the intravenous route to patients suffering from susceptible neoplasms. The usual pharmceutical formulation employed has been a lyophilized vial of a sulfate salt which is reconstituted prior to use. The sulfate salts are prepared by adding a theoretical amount of sulfuric acid to a solution of the alkaloidal free base. In the case of vindesine, however, the sulfate made by the ordinary procedure is not stable and a special sulfate disclosed in U.S. Pat. No. 4,259,242 must be employed in the lyophilized pharmaceutical formulation.
It has long been felt desirable to have ready-to-use solutions of vincristine sulfate or other vinca alkaloids for several reasons. In the first place, improper reconstitution of a lyophilized product sometimes results in the formation of air-borne droplets which may be a hazard to the hospital personnel who are making up the solution for an i.v. injection. Vincristine is an extremely potent oncolytic drug and it would seem to be simple common sense to avoid contact with this drug insofar as possible. Furthermore, avoiding all contact with any cytostatic drug and especially vincristine is desirable. In addition, there is always a problem in reconstituting a lyophilized formulation in that an inappropriate quantity of diluent may be used or that an incorrect amount of drug may be used because of a different vial size. The margin between toxic effects and therapeutic dose is relatively small with the vinca alkaloids. Errors in concentration for i.v. injection resulting in accidental overdosages with vincristine have been recorded in the literature. See for example the Journal of Pediatrics, 89, 671 (1976), Cancer Chemotherapy Reports, 55, 525 (1972), and Journal of Pediatrics, 90, 1042 (1977).
Another disadvantage of the lyophilized vincristine sulfate arises from the mode of calculating dose levels for each individual. Vincristine sulfate is supplied in even milligram amounts (e.g., 1 mg. and 5 mg. vials). Since a dose is usually calculated as 2 mg. per square meter of body surface for children and 1.4 mg. per square meter body surface for adults, the doses actually given are usually in decimal milligram amounts, and therefore only part of a vial's contents may be given. In addition, it should be reiterated that there is a narrow margin between the toxic dose and the effective dose of vincristine. Thus, since the dosage is actually calculated in treating humans for leukemias, lymphomas, etc. for which vincristine is recommended as an oncolytic agent, there will ordinarily be some excess of reconstituted vincristine left over after a given treatment. This problem is not particularly serious in a large cancer clinic where there is a daily use of vincristine and what is left over from one patient can be applied to the next. However, the recommended life for reconstituted vincristine is 14 days at refrigerated temperature. Thus, there will be a necessity in many instances for discarding excess reconstituted lyophilized vincristine which has outlived its 14 day dating period. Vincristine is an extremely expensive drug and any amount of it which must be discarded will naturally increase the overall cost of maintaning a cancer clinic.
The physical changes noticed on standing with reconstituted lyophilized vincristine (reconstituted with 0.9% aqueous sodium chloride containing benzyl alcohol as a preservative) are a general haziness of the solution followed by the appearance of a precipitate.
Another problem is the need to incorporate a preservative into any vincristine solution formulation in order to prevent the growth of microorganisms. In general, vincristine solutions cannot be heat sterilized but can be sterilized by filtration. However, even if the latter process is used, a preservative must be present in the diluent used to reconstitute the lyophilized material or in an opened previously sterilized liquid vial because of the possibility of contamination from the air. Otherwise, the excess material would have to be discarded immediately and could not be kept even for the 14 day period discussed above.
Reconstituted solutions of vinblastine sulfate and vindesine sulfate possess similar problems and concerns although because both compounds contain an N-methyl group instead of the more liable N-formyl functionality found in vincristine, the stability problems are less severe as evidenced by a recommended reconstituted stability dating of thirty days.
It is an object of this invention to provide stable, ready-to-use solutions of oncolytic vinca alkaloids for i.v. injection whose use would minimize the contact between hospital personnel and the drug and would provide a single solution strength for all vial and syringe sizes employed thus avoiding error in reconstitution.